The present invention relates to agents and methods for treating cancer, particularly prostate cancer as well as other cancers, particularly androgen-insensitive cancers, in humans.
The mainstay of treatment for metastatic prostate cancer is hormonal or endocrine therapy (Kozlowski, J. M. et al. Urol. Clin. North Am. 18: 15–24 (1991), and Balmer, C. et al., Finley, R. S. and Balmer, C. (eds.), Concepts on Oncology Therapeutics, pp. 211–229, Bethesda: ASHP (1998)). It is aimed at androgen ablation by interfering either with androgen production or with the action of androgen within prostate cancer cells. Biochemical and morphological evidence has demonstrated that hormone ablation induces an active process that leads to apoptosis (programmed cell death) in androgen-sensitive prostate cancer cells (Kyprianou, N. Cancer Res. 50: 3748–53 (1990)). However, if a patient's prostate cancer progresses while receiving the first-line hormonal therapy, or if the patient never responds to the first-line hormonal his cancer is classified as androgen-insensitive or hormone-refractory prostate cancer (HRPC) (Kypianou, N. World J. Urol. 12: 299–303 (1994) and Bosland, M. C., Bertino, J. R. (ed.) Encyclopedia of Cancer, Vol. 2, pp. 1283–96, New York: Academic Press (1997)). Although the mechanism underlying the progression to an androgen-independent state remains elusive, it has been associated with the overexpression of the anti-apoptotic protein Bcl-2 or with abnormalities of the pro-apoptotic protein p53. Despite apoptosis resistance, androgen-independent prostate cancer cells still retain the basic machinery required for apoptosis. Nevertheless, HRPC always has a fatal outcome because the currently available chemotherapy regimens have limited impact on the survival of patients with HRPC (Kozlowski, J. M. et al. Urol. Clin. North Am. 18: 15–24 (1991), and Tannock, I. F. J. Clin. Oncol. 3: 1013–21 (1985)).
There remains a long-felt need for drugs that can induce apoptosis in patients with hormone refractory cancers such as HRPC. These drugs should work independent of androgen responsiveness, Bcl-2 levels, and p53 functional status. These drugs should have a high potency in inducing apoptosis in cancer cells while not adversely affecting normal cells. These drugs should further be well tolerated in humans and have few, if any, side effects.